Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PP3, BS1, BS2
Clinical Phenotype: Alzheimer's Disease, None, Parkinson's Disease Dementia
Reference Assembly: GRCh37/hg19
Position: Chr1:227073271 C>T
dbSNP ID: rs63750197
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TCG to TTG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6


The S130L variant has been detected in several Alzheimer's disease patients with a family history of disease, most having early-onset presentation. However, evidence for segregation with disease is lacking, and the variant is present in the gnomAD variant database at a moderately high frequency (allele count = 187, frequency = 0.0006620; v2.1.1, Nov 2021) and in HEX, a database of variants from people age 60 or older who did not have a neurodegenerative disease diagnosis or disease-associated neuropathology at the time of death (allele count = 2, frequency = 0.0021, Nov 2021).

The S130L variant was first reported in a kindred from northern Italy (FL056) (Sorbi et al., 2002; Tedde et al., 2003). The proband experienced symptom onset, chiefly memory loss, at age 65. The proband had a family history of dementia, with an affected mother, uncle, and grandfather. Onset age was 65 for the mother and uncle, and unknown for the grandfather. In this family the clinical presentation was characterized by a long disease duration, with many years of mild cognitive impairment before the development of bona fide dementia. Segregation with disease could not be determined.

This variant was also identified in a patient with apparent late-onset, sporadic AD (Tomaino et al., 2007). This patient had disease onset at age 81 with progressive memory impairment and spatial disorientation, as well as mood and personality changes. He rapidly developed language deficits, agitation, delusions, hallucinations, agnosia, aphasia, and mild bradykinesia. Two of the proband's siblings were reported to have Parkinson's disease, but were cognitively healthy. Segregation with disease could not be determined.

The S130L variant was detected in a Turkish individual who developed late-onset AD (Lohmann et al., 2012). His symptoms started at age 77, with depression, progressive memory impairment, and episodes of spatial disorientation. He also developed mild bradykinesia. His mother and maternal uncle were also affected by memory problems. Segregation with disease could not be determined.

In addition, the variant was reported in a woman with probable AD in the U.S. (Wojtas et al., 2012). The carrier’s first clinical symptom, reported at age 52, was memory loss. She had no known history of dementia. She had an APOE3/3 genotype.

The S130L variant was also one of several rare variants detected by exome sequencing in a British cohort composed of 47 unrelated, early onset AD cases and 179 elderly controls free of AD pathology. The variant was detected in one AD case and one control case. The AD patient developed cognitive symptoms at age 61 and died at age 65 with autopsy-confirmed AD. The precise age of the elderly control case was not reported (Sassi et al., 2014).

This variant was also reported in an individual with idiopathic Parkinson’s disease with dementia (Schulte et al., 2015). This individual first developed symptoms at age 73, beginning with bradykinesia. Later symptoms included resting tremor, rigor, postural instability, and dementia.

In a recent study using whole-exome sequencing, this variant was identified in three of 424 French people with early onset AD (Nicolas et al., 2015). Associated clinical data were limited for these individuals. Two of the S130L carriers had apparently sporadic AD with onset at ages 51 and 62, respectively. The third individual had a family history of dementia; however, segregation with disease could not be assessed. This individual was 65 at onset and had an APOE genotype of E3/E3.

In addition to the germ-line mutations described above, this variant was also one of three mosaic mutations detected in AD-related genes in the brain by deep sequencing (Sala Frigerio et al., 2015). Of the 130 entorhinal cortex samples analyzed, the S130L variant was detected in one control sample at an allelic frequency of about 1 percent. This individual died at age 90 with mild AD pathology (modified Braak stage II). The significance of a low frequency mosaic mutation in the brain is currently unclear.

The S130L variant is also associated with dilated cardiomyopathy in at least two families, although penetrance is incomplete (Li et al., 2006).


At least one affected mutation carrier had neuropathology consistent with AD at autopsy (Sassi et al., 2014). In addition, Aβ43/Aβ40 and Aβ42/Aβ40 ratios were decreased in the CSF of a Belgian carrier with an APOE3/E3 genotype (Perrone et al., 2020). Also, in this same individual, Aβ40, Aβ42, Aβ43, sAPPα, sAPPβ levels were reduced. Tau and phospho-tau levels were comparable to those of controls.

Biological Effect

Despite the reduced CSF Aβ43/Aβ40 and Aβ42/Aβ40 ratios described above, in vitro studies suggest a lack of an effect of S130L on APP processing. When transfected into fibroblasts lacking endogenous PSEN1 and PSEN2, the S130L variant did not affect levels of the proteolytic products PSEN2-CTF and PSEN2-NTF compared with wild-type PSEN2, indicating that the substitution does not alter steady-state endoproteolytic activity. In addition, when co-transfected with APP carrying the Swedish mutation, the S130L mutation did not affect Aβ42 levels or the Aβ42/Aβ40 ratio (Walker et al., 2005). Calcium signaling was altered in cultured skin fibroblasts from mutation carriers. Specifically, the resting intracellular calcium concentration was elevated (Li et al., 2006).

Consistent with these experimental results, computer modeling of PSEN2 structure and function predicted only minor effects on Aβ42 and Aβ40 production, but inhibition of the phosphorylation of S130 by protein kinase C, resulting in disruption of calcium signaling (Soto-Ospina et al., 2021). Moreover, in silico analyses have predicted the S130L variant to be "possibly damaging" (Sassi et al., 2014; Lohmann et al., 2012, Hsu et al., 2020) or "damaging" (Hsu et al., 2020). Also, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021). This residue is not conserved between PSEN2 and PSEN1.

Lohmann and colleagues classified S130L as "probably pathogenic" based on the algorithm proposed by Guerreiro et al. (Lohmann et al., 2012; Guerreiro et al., 2010) and Perrone et al. described it as "likely pathogenic" citing Lohmann's classification and the reduced CSF Aβ43/Aβ40 and Aβ42/Aβ40 ratios (Perrone et al., 2020). In contrast, Hsu and colleagues predicted the variant is either “not pathogenic” or a  “risk factor” (Hsu et al., 2020).


Alzheimer's Disease : Uncertain Significance*

*This variant may be a risk factor, a classification not included in the ACMG-AMP guidelines.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.


Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. S130L: Lack of functional effect on APP processing, but altered calcium signaling.


The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. S130L: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. S130L: Variant is at a location predicted to inhibit PKC phosphorylation and disrupt calcium signaling.


Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.


Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  S130L: Most carriers were of European ancestry.


Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 22 Feb 2022


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Paper Citations

  1. . Novel presenilin 1 and presenilin 2 mutations in early-onset Alzheimer's disease families. Neurobiol Aging. 2002 Jul-Aug;23(1S):312.
  2. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.
  3. . Presenilin 2 Ser130Leu mutation in a case of late-onset "sporadic" Alzheimer's disease. J Neurol. 2007 Mar;254(3):391-3. PubMed.
  4. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
  5. . C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic. Am J Neurodegener Dis. 2012;1(1):107-18. Epub 2012 May 16 PubMed.
  6. . Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2422.e13-6. Epub 2014 May 2 PubMed.
  7. . Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.
  8. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.
  9. . Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet. 2006 Dec;79(6):1030-9. Epub 2006 Oct 24 PubMed.
  10. . Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.
  11. . Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem. 2005 Jan;92(2):294-301. PubMed.
  12. . Structural Predictive Model of Presenilin-2 Protein and Analysis of Structural Effects of Familial Alzheimer's Disease Mutations. Biochem Res Int. 2021;2021:9542038. Epub 2021 Nov 29 PubMed.
  13. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
  14. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Other Citations

  1. HEX

Further Reading

Protein Diagram

Primary Papers

  1. . Novel presenilin 1 and presenilin 2 mutations in early-onset Alzheimer's disease families. Neurobiol Aging. 2002 Jul-Aug;23(1S):312.
  2. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.


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